The dominant therapeutic approaches that are currently employed to treat cancer include surgical removal of primary tumors, tumor irradiation, and parenteral application of anti-mitotic cytotoxic agents. The continued dominance of long established therapies is mirrored by the lack of improvement in survival rates for most cancers. Surgical intervention often results in a release of tumor cells into the circulation or lymph systems from which metastatic tumors can subsequently be established.
Resistance of tumor cells to chemotherapeutic drugs is an important problem in the clinical management of cancer. Paclitaxel is an anti-mitotic cytotoxic agent that has provided improvement in patient outcomes. Unfortunately, despite this success, many patients will eventually progress to a phase of the disease that becomes resistant or unresponsive to treatment with paclitaxel and other traditional chemotherapeutic drugs.
The compounds useful in the present invention have been disclosed as inhibitors of fatty acid synthesis in U.S. Publication No. 2012/0264737, International PCT Publication No. WO 2015/105860, and International PCT Publication No. WO 2014/008197, which are incorporated herein by reference in their entirety. Surprisingly, the compounds of the present disclosure have been found to be useful to resensitize paclitaxel-resistant cancers to treatment with paclitaxel or Nab-paclitaxel.